Synthesis of nitrophenyl and fluorophenyl azides and diazides by SNAr under phase-transfer or microwave irradiation: Fast and mild methodologies to prepare photoaffinity labeling, crosslinking, and click chemistry reagents

Article abstract of DOI:10.1002/poc.4171

Two fast and mild methodologies to prepare nitrophenyl and fluorophenyl azides are presented. These aryl azides are extensively used as crosslinking, photoaffinity labeling, and click chemistry reagents. Substituted aryl azides are prepared by performing a S_NAr substitution on halogenated benzenes with a phase-transfer catalyst (PTC) such as tetraethylammonium tetrafluoroborate (TEATFB), the reaction proceeds in several hours under rather mild temperatures (25°C to 70°C). Furthermore, aryl azides are also prepared within minutes under microwave irradiation at slightly higher temperatures (50°C to 70°C). These procedures could be applied in the preparation of other aryl azides. In the case of substituted pentafluoro benzene (pF), the type of products obtained in each reaction depends on the amount of sodium azide and the strength and position of electron-withdrawing substituents (COH, COR, COOR, CN, NO₂, or F). A discussion on the mechanisms and the products obtained in these S_NAr reactions is presented.

Full text of DOI:10.1002/poc.4171

Received: 19 May 2020
DOI: 10.1002/poc.4171
Revised: 2 November 2020
Accepted: 4 November 2020
R E S E A R C H A R T I C L E
Synthesis of nitrophenyl and fluorophenyl azides and
diazides by SNAr under phase-transfer or microwave
irradiation: Fast and mild methodologies to prepare
photoaffinity labeling, crosslinking, and click
chemistry reagents
Elisa Leyva
| Johana Aguilar | Regina M. González-Balderas |
Sarai Vega-Rodríguez | Silvia E. Loredo-Carrillo
Facultad de Ciencias Químicas,
Abstract
Universidad Autónoma de San Luis
Potosí, San Luis Potosí, SLP, Mexico
Two fast and mild methodologies to prepare nitrophenyl and fluorophenyl
azides are presented. These aryl azides are extensively used as crosslinking,
photoaffinity labeling, and click chemistry reagents. Substituted aryl azides are
prepared by performing a SNAr substitution on halogenated benzenes with a
phase-transfer catalyst (PTC) such as tetraethylammonium tetrafluoroborate
(TEATFB), the reaction proceeds in several hours under rather mild tempera-
tures (25ꢀC to 70ꢀC). Furthermore, aryl azides are also prepared within
minutes under microwave irradiation at slightly higher temperatures (50ꢀC to
70ꢀC). These procedures could be applied in the preparation of other aryl
azides. In the case of substituted pentafluoro benzene (pF), the type of prod-
ucts obtained in each reaction depends on the amount of sodium azide and the
strength and position of electron-withdrawing substituents (COH, COR,
COOR, CN, NO2, or F). A discussion on the mechanisms and the products
obtained in these SNAr reactions is presented.
Correspondence
Elisa Leyva, Facultad de Ciencias
Químicas, Universidad Autónoma de San
Luis Potosí, Manuel Nava No. 6, San Luis
Potosí, SLP 78290, Mexico.
Email: elisa@uaslp.mx
Funding information
CONACyT, Grant/Award Numbers:
155678, CVU 1007105
K E Y W O R D S
aryl azide, crosslinker, microwave, phase-transfer catalyst, photoaffinity labeling, SNAr
1 | INTRODUCTION
applications in several areas of chemistry such as synthe-
sis of heterocyclic compounds,[4] polymer chemistry as
Aryl azides are high-energy molecules with interesting
photochemical and thermochemical properties.[1] Their
complex chemistry has fascinated scientists for many
years.[2] Spectroscopists have investigated the intermedi-
ates formed in the photochemistry of aryl azides by fast
and high-resolution techniques. Theoretical chemists
have studied the intrinsic interplay of intermediates
formed under different reaction conditions.[3] Nitro- and
crosslinking agents,[5] and biochemistry as photoaffinity
labeling reagents.[6] Due to their physicochemical proper-
ties, fluorophenyl azides have been applied in different
areas of organic and material science.[7] They have been
used in coupling polymers and other carbon materials to
organic substrates and nanoparticles where a wide range
of materials could be efficiently modified.
Aryl azides are usually prepared by treatment of dia-
zonium salts with sodium azide.[8] Because this
fluoro-substituted
aromatic
azides
have
found
J Phys Org Chem. 2020;e4171.
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https://doi.org/10.1002/poc.4171

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LEYVA ET AL.
methodology has some limitations, several alternative
procedures have been investigated. They are also
prepared reacting Grignard reagents and aryl amide salts
with p-toluenesulfonyl azide.[9] A potentially explosive
reagent, triflyl azide has been used in the conversion of
aromatic amines into the corresponding azides.[10]
Upon refluxing with sodium azide, pentafluorobenzene
2 | RESULTS AND DISCUSSION
First, the SNAr reaction was performed under conven-
tional heating and para-fluoro nitrobenzene was reacted
with sodium azide by refluxing in several solvent mix-
tures such as acetone/water, CHCl3/water, and
DMF/water. Because the reaction proceeded only with a
DMF/water mixture, it must require a rather polar
solvent.[11] Thus, several para-halogen nitrobenzene
derivatives (Scheme 1) were reacted with sodium azide in
DMF/water for several hours (10 to 20) at mild tempera-
tures (55ꢀC or 70ꢀC). Because sodium azide is not soluble
in DMF, an aqueous solution of sodium azide
(1 mmol/2 ml H2O) was combined with an organic solu-
tion of the halogenated benzene (1 mmol/6 ml DMF).
The flask containing the reaction mixture was stirred and
kept in a hot water bath. In each case, the temperature
reported was found to be the minimum temperature to
perform the substitution (Table 1). Each mixture was
analyzed by TLC, and when the reaction was completed,
a volume (20 ml) of cold water was added to induce the
precipitation of the aryl azide. The product was separated
by filtration, purified, and characterized. In the case
where the leaving halogen has a small size and strong
electron-withdrawing properties like a fluoro atom, the
reaction proceeds at lower temperature (55ꢀC) and
within 10 h. Having a larger size and weaker electron-
withdrawing leaving substituent like Iodo increases the
reaction temperature (70ꢀC) and the reaction time
considerably, from 10 to 20 h.
Nucleophilic aromatic substitution reactions (SNAr)
have been investigated for many years. Classical SNAr
reactions of aryl halides were demonstrated to take place
when a strong electron-withdrawing group like a nitro is
located ortho or para to the leaving halogen atom.[18] Up
to 2013, the generally accepted mechanism involved an
addition–elimination process with an intermediate
Meisenheimer complex (Scheme 2). This intermediate
was easily formed under SNAr conditions because it is
stabilized by the presence of a nitro group. Further
evidence of this mechanism is the fact that a fluorine is
a faster leaving group.[18] Therefore, milder conditions
containing
an
electron-withdrawing
substituent
(cyano, nitro, or carbonyl) undergoes selective aromatic
para-substitution.[11] The preparation of several activated
aryl and heteroaryl azides by nucleophilic aromatic
substitution in an ionic liquid solution has also
been reported.[12] All of these procedures require long
reaction times, nonavailable reagents, and harsh condi-
tions such as high temperatures, strong acids, or strong
bases.
In search of milder conditions, an alternative prepara-
tion of para-substituted fluorophenyl azides by SNAr
under microwave irradiation mw was recently reported
by us.[13] In the present investigation, this procedure is
applied to the preparation of several nitro- and
fluoro-substituted aryl azides. The application of
microwave irradiation mw as a source of energy for reac-
tions as become a convenient technique for organic
chemistry. In general, the use of this type of energy
results in enhanced conversion rates and cleaner
reactions demonstrating the practical advantages of this
methodology.[14]
SNAr reactions are heterogeneous processes involving
the reaction of an aromatic substrate in an organic phase
and an inorganic salt in an aqueous phase. In this partic-
ular case, an organic solution (halogenated benzene in
acetone or DMF) is mixed with an inorganic solution
(sodium azide in water). In order to make these reactions
to proceed, high temperatures and long reaction times
are usually required.[11] Therefore, these aromatic
substitution reactions could be improved utilizing a
phase-transfer catalyst (PTC) to favor transfer an
inorganic salt into an aromatic mixture.[15] The use of a
PTC catalyst (tetraethylammonium tetrafluoroborate
[TEATFB]) in the SNAr reaction of ortho-halogenated
nitrobenzenes has been recently reported.[16]
In general, azido compounds have to be considered
and handled as explosive materials. Organic and aryl
azides have remarkable lower ignition temperatures in
comparison with inorganic metal azides.[17] Because
nitrophenyl and fluorophenyl azides easily decompose
with heat, it is important to develop methods to prepare
them using mild and homogeneous temperatures. In this
paper, two different SNAr methodologies, phase-transfer
conditions and microwave irradiation, were investigated
for the preparation of nitrophenyl and fluorophenyl
azides and diazides.
were
usually
required
with
fluoro-substituted
SCHEME 1 Synthesis of aryl azides by SNAr under different
experimental condition

LEYVA ET AL.
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TABLE 1 Yields of nitrophenyl and fluorophenyl azides under different experimental conditions
Mild t, no PTCa
Mild t, with PTCb
mwc
t
Time
Yield
(%)
t
Time
Yield
(%)
t
Time
Reagent
Aryl azide
(ꢀC) (h)
(ꢀC) (h)
(ꢀC) (min)
Yield (%)
55
60
70
70
55
10
12
16
20
10
85
70
60
60
80
55
60
70
70
55
4
6
91
75
65
65
90
70
70
70
70
70
10
30
50
20
25
85
75
70
70
70
8
10
4
60
50
50
50
12
10
12
12
80
80
80
70
60
50
50
50
6
85
85
81
75
70
50
50
50
40
70
85
82
83
4
5
6
5
6
5
(Continues)

4 of 12
LEYVA ET AL.
TABLE 1 (Continued)
Mild t, no PTCa
Time
Mild t, with PTCb
mwc
t
Yield
(%)
t
Time
Yield
(%)
t
Time
Reagent
Aryl azide
(ꢀC) (h)
(ꢀC) (h)
(ꢀC) (min)
Yield (%)
50
12
70
70
6
75
70
5
76
50
50
50
50
40
12
12
12
12
10
80
81
75
80
80
50
50
50
50
40
6
6
6
6
4
92
90
91
76
90
70
70
70
70
70
5
87
5
80
5
80
5
85
15
85 (Leyva
et al.[13]
)
)
)
40
40
10
10
80
80
40
40
4
4
85
85
70
70
15
15
85 (Leyva
et al.[13]
70 (Leyva
et al.[13]
(Continues)

LEYVA ET AL.
5 of 12
TABLE 1 (Continued)
Mild t, no PTCa
Time
Mild t, with PTCb
mwc
t
Yield
(%)
t
Time
Yield
(%)
t
Time
Reagent
Aryl azide
(ꢀC) (h)
(ꢀC) (h)
(ꢀC) (min)
Yield (%)
25
12
85
25
4
4
95
70
15
90 (Leyva
et al.[13]
)
25
12
85
25
95
70
15
90 (Leyva
et al.[13]
)
aA mixture of halogenated benzene (1 mmol) in DMF or acetone (6 ml) and sodium azide (1 mmol) in water (2 ml) was reacted at mild temperature.
bA mixture of halogenated benzene (1 mmol) in DMF or acetone (6 ml) and sodium azide (1 mmol) and TEATB (0.1 mmol) in water (2 ml) was reacted at mild
temperature.
cA mixture of halogenated benzene (1 mmol) in DMF or acetone (6 ml) and sodium azide (1 mmol) in water (2 ml) was irradiated in a microwave reactor
(Discover CEM, 50 W) at mild temperature.
nitrobenzenes. The leaving group ability for SNAr reac-
tions is different from the one observed in nucleophilic
substitution at a saturated carbon. In aryl halides, fluoro
is a better leaving group than any of the other halogens.
The main reason for the order I > Br > Cl > F in regular
SN2 reactions is the strength of carbon–halogen bond
(increasing from I to F). This physicochemical property is
not important in a reaction involving a SNAr mechanism,
because bond breaking is not part of the rate-determining
step (Scheme 2). Furthermore, the highly electronegative
fluoro atom favors the addition step making the reacting
carbon highly positive.[19]
a concerted mechanism.[20] In these latter examples, sub-
stitution reactions could occur even without the presence
of a highly activating substituent like a nitro group.
Therefore, further investigations are required to expand
the scope of reactions involving a SNAr mechanism open-
ing the possibility to prepare novel aromatic compounds.
Under similar experimental conditions, ortho-
nitrophenyl azide (Table 1) was obtained in good yields
(80%) when the leaving group was a chloro or fluoro
atom. This procedure was also applied in the preparation
of other nitrophenyl derivatives; several substituted
2-nitrophenyl, 2,4-dinitrophenyl, and 2,6-dinitrophenyl
azides were also prepared. Experimentally, lower temper-
atures were required to initiate the reaction when two
electron-withdrawing substituents are present in ortho-
and/or para-position due to enhanced inductive effects.
However, the presence of two nitro substituents ortho to
the leaving halogen required longer reaction times and
lower yields of azides (70%) were obtained. All of this is
due to enhanced steric effects in the first step of the SNAr
mechanism.
In recent years, several studies have demonstrated
that many SNAr reactions could actually proceed through
All the above SNAr substitution reactions were also
investigated under phase-transfer conditions. To do this,
all the reactions were performed at the same experimen-
tal conditions (Table 1) in the presence of a PTC,
TEATFB salt (0.1 mmol). In each case, the crude mixture
was analyzed by thin-layer chromatography, and it was
observed that the reaction was cleaner and proceeded
very fast. When the reaction was completed, a volume
SCHEME 2 Addition–elimination mechanism for a classical
SNAr reaction for para-halogenated nitrobenzene with sodium
azide

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LEYVA ET AL.
(20 ml) of cold water was added to induce the precipita-
tion of the aryl azide. The crystalline product was
separated by filtration, recrystallized in ethanol, and
characterized.
It is well known that all quaternary ammonium salts,
like TEATFB, act as PTCs.[15] This particular SNAr reac-
tion is an example of a biphasic phase-transfer process
where the catalyst accelerates the reaction by solubilizing
the azide ion (N3−) into the organic phase (Scheme 3).
Under phase-transfer conditions, this azide ion is in close
contact with the halogenated benzene and the reaction
takes place faster. The fact that all reactions proceed
faster clearly indicates a catalytic effect (Table 1).
In the case of substituted pentafluoro benzene (pF)
derivatives, the SNAr reaction was also investigated under
conventional heating and each derivative was reacted
with sodium azide by refluxing in several solvent
mixtures such as acetone/water, CHCl3/water, and
DMF/water. Due to polarity of the pentafluoro deriva-
tives, the reaction only proceeded with a mixture of
acetone/water.[11] Because sodium azide is not soluble in
acetone, these substitution reactions were performed
with some modifications (Table 1). An organic solution
of a pF (1 mmol) in acetone (6 ml) was combined with
an inorganic solution of sodium azide (1 mmol) in water
(2 ml). The reaction mixture was stirred for several
hours (10 to 12) and kept in a hot water bath at 25ꢀC or
40ꢀC. Experimentally, it was found that this was the min-
imum temperature to perform the reaction for these
highly activated derivatives. Having a very strong
electron-withdrawing group like a CN or nitro in the
para-position of the carbon containing the leaving fluoro
atom, makes the reaction to proceed at room temperature
(25ꢀC) with rather high yields (85%). The reaction was
monitored by TLC and when it was completed, a volume
(20 ml) of cold water was added. The reaction mixture
was extracted with ether and the organic extract
was dried, filtered, and concentrated. Each aryl azide
was purified by column chromatography. Performing the
same substitution reactions on pF derivatives under
phase-transfer conditions, shorter reactions times (4 h)
were required and cleaner products were obtained
(Table 1).
There are many reports about the use of mw irradia-
tion in the synthesis of
a
variety of organic
compounds.[14,21–26] They provide information about
basic theory and equipment to perform reactions with
mw. Heating with this type of energy depends on the
property of several materials to absorb this energy and
convert it into heat. Two basic mechanisms operate:
dipolar polarization and ionic induction. Upon mw
irradiation, dipoles and ions in a reaction mixture align
with the applied electric field. Because this field oscil-
lates, dipole and ion fields attempt to realign themselves
and, consequently, energy is converted into heat upon
molecular friction and dielectric energy lost. In a mw
process, the amount of heat is directly proportional to the
capacity of a given field to align itself with the frequency
of the applied field. The frequency in all commercial
instruments is just sufficient to allow for molecular
dipoles and ions to align with the applied field. Under
these experimental conditions, rapid and homogeneous
heating of reaction mixtures is achieved. In the bulk of a
given reaction mixture under mw heating, an inverted
gradient is achieved in comparison with conventional
heating. Several studies have demonstrated the higher
energy efficiency obtained upon mw heating.[27–29]
Because the preparation of some para-substituted
fluorophenyl azides using mw irradiation has been
reported,[13] this procedure was also applied in the prepa-
ration of several nitrophenyl azides (Table 1). To start
these experiments, a solution of a para-halogenated
nitrobenzene (1 mmol) in DMF (6 ml) and a solution of
sodium azide (1 mmol) in water (2 ml) were placed in a
flask. The resulting mixture was placed in a mw reactor
and irradiated for several minutes (10 to 50). In all the
experiments, TLC analysis of reaction mixtures indicated
the reactions proceeded very fast and clean. After cooling,
the mixture was poured into a volume (20 ml) of cold
water. It was extracted with ether and the organic extract
was dried, filtered, and concentrated. Each aryl azide was
purified by column chromatography.
Contrasting results were observed in the preparation
of para-nitrophenyl azide under mw irradiation
(Table 1). In agreement with the classical SNAr mecha-
nism, reaction time increased when the reaction was per-
formed with a nitrobenzene containing a halogen with
increasing atom size and decreasing electronegativity
(F > Cl > Br).[19] However, the reaction of a nitrobenzene
containing a larger Iodo atom was faster than the reac-
tion of the same aromatic compound containing another
smaller halogen (I > Cl > Br). Under mw irradiation, the
large Iodo atom is strongly polarized and the C–I bond
becomes weak. This polarization effect could easily
SCHEME 3 SNAr reaction of halogenated benzene with
sodium azide under phase-transfer conditions

LEYVA ET AL.
7 of 12
SCHEME 4 Concerted mechanism for a SNAr
reaction for p-Iodo nitrobenzene with sodium azide
under mw irradiation
induce a change on the mechanism involving a concerted
process for the Iodo derivative (Scheme 4). This type of
mechanism has been demonstrated to occur in some
SNAr reactions by means of computational studies.[20]
The preparation of other nitro-substituted aryl azides
under mw irradiation was also investigated (Table 1).
Halogenated benzenes containing two electron-
withdrawing groups reacted very fast (5 min). Under
these mild conditions, also the pF compounds reacted
rather fast (15 min). Because all these pF compounds are
highly activated for SNAr substitution,[13] the effect of the
amount of sodium azide in the products obtained was
also investigated. Instead of using an equivalent molar
ratio (1 mmol of azide/1 mmol of pF), an excess of
sodium azide was added.
Under different experimental conditions, reacting a
pF containing a weakly activating substituent (COH or
COCH3), with an excess of sodium azide (5 mmol of
azide/1 mmol pF), results in the exclusive formation of
para-substituted perfluoro aryl azide (Scheme 5).
Therefore, this particular pF reacts only by one pathway
because only the para-position is sufficiently activated for
the reaction to take place (Route 1, Scheme 6).
The reaction of a pF (1 mmol) containing a medium
electron-withdrawing substituent (COOR) with an excess
of sodium azide (5 mmol) results in the formation of a
mixture of products (Scheme 7). For this particular
reagent, two energy pathways are close in energy and
compete (Routes 1 and 2, Scheme 6). Reacting an amount
(1 mmol) of a pF (derivative containing a strong
electron-withdrawing group [nitro or cyano]) with an
excess of sodium azide (5 mmol) gave two products
SCHEME 5 Product obtained in the reaction of pF
compounds (R = COH, COCH3) with an excess of sodium azide
under different experimental conditions
SCHEME 6 Products obtained in the reaction of pF
compounds with an excess of sodium azide under a classical
SNAr mechanism
SCHEME 7 Products obtained in the reaction of pF
compound (R = COOCH3) with an excess of sodium azide
under different experimental conditions

8 of 12
LEYVA ET AL.
(Scheme 8) essentially monoazide and diazide under
different experimental conditions. Once the first substitu-
tion takes place, a para-substituted (CN or NO2) phenyl
azide contains two ortho-positions strongly activated for a
second substitution to take place (Route 3, Scheme 6).
Based on the products obtained in these SNAr reac-
tions, three different free energy diagrams are proposed
(Figure 1). Under mild experimental conditions, for the
pF compound containing a COH or COR only one energy
route is available (Figure 1A). For the pF containing
COOR, two compounds are obtained; therefore, two
pathways close in energy compete (Figure 1B). In the
case of a pF with NO2 or CN, once the low energy para-
substituted azide is formed (Figure 1C), it reacts to give
the diazide. It has been reported in the literature that
reactions proceeding by a classical SNAr mechanism are
accelerated by electron-withdrawing groups specially
when these groups are located in para-position. The
activating ability has been measured in terms of the
substituent (NO2 > CN > COOR > COH > COR).[30]
Contrasting results were obtained with 2,3,4-trifluoro-
1-nitrobenzene. In this particular case, a complex
mixture, containing the starting material, an azide and
diazide (Scheme 9), was obtained even when the reaction
was performed with an equivalent amount of sodium
azide (1 mmol of azide/1 mmol of 2,3,4-trifluoro-1-nitro-
benzene). Thus, to investigate which product was
favored, the reaction was performed with a large excess
(5 mmol) of sodium azide. In this latter experiment, the
diazide was obtained in greater yields (Scheme 9).
SCHEME 8 Products obtained in the
reaction of pF compounds (R = CN, NO2)
with an excess of sodium azide under
different experimental conditions
FIGURE 1 Proposed free energy diagrams for the SNAr
reactions of sodium azide with different pF compounds.
(A) R = COH, COCH3; (B) R = COOCH3; and
(C) R = CN, NO
SCHEME 9 Products obtained in the reaction of 2,3,4-trifluoro-1-nitrobenzene with an excess of sodium azide under different
experimental conditions

LEYVA ET AL.
9 of 12
FIGURE 2 Proposed free energy diagrams for the
SNAr reactions of sodium azide (A) with symmetric
pentafluoro nitrobenzene and (B) with asymmetric
2,3,4-trifluoro-1-nitrobenzene
Based on the products obtained in the reaction of
each nitro- and fluoro-substituted benzene, two
different free energy diagrams are proposed (Figure 2).
In para-nitro-tetrafluorophenyl azide, there are two
positions (ortho to nitro) equally activated for a second
substitution to take place (Figure 2A). In the case of
2,3,4-trifluoro-1-nitrobenzene, once the asymmetric
mono azide is obtained, it contains one exclusive
position (ortho to nitro) that is strongly activated
towards a second substitution and the formation of the
reaction proceeds within hours under rather mild
temperatures (25ꢀC to 70ꢀC). Performing the same
SNAr substitution under mw irradiation, the reaction
proceeds within minutes at slightly higher tempera-
tures (50ꢀC to 70ꢀC).
In substituted pFs, the type of products obtained
depends on the amount of sodium azide and
the strength and position of electron-withdrawing
substituents (COH, COR, COOR, CN, NO2 and F).
Performing the reaction with an equivalent amount of
sodium azide (1 mmol of azide/1 mmol of pF) results
in the exclusive formation of para-substituted
tetrafluoro benzene. Having an excess of sodium azide
(5 mmol of azide/1 mmol of pF) results in the forma-
tion of different products. A pF containing a weak
electron-withdrawing group (COH and COR) gives
only the para-substituted tetrafluorophenyl azide. A pF
with a medium strength group (COOR) gives two
monosubstituted (ortho and para) phenyl azides.
diazide becomes
a
rather lower energy process
(Figure 2B). In polymer modifications and material
science diazide compounds are particularly important
for crosslinking experiments.[3]
3 | CONCLUSION
In conclusion, we developed two mild and fast meth-
odologies to prepare nitrophenyl and fluorophenyl
azides; these compounds are extensively used as a
crosslinking, photoaffinity labeling, and click chemistry
reagents. Performing a SNAr substitution on haloge-
nated benzenes with a PTC such as TEATFB, the
Having
a
strong electron-withdrawing substituent
(CN or NO2) in symmetric R-pentafluorobenzene
results in the formation of two products, the
para-azide (60%) and the disubstituted (ortho- and
para-) azide (30%). In contrast, having
a nitro

10 of 12
LEYVA ET AL.
substituent in asymmetric 2,3,4-trifluoro-1-nitrobenzene
results in the formation of a small amount (30%) of
4.2 | Preparation of nitrophenyl azides
by SNAr reaction under conventional
heating
monoazide (4-azido-2,3-difluoro-nitrobenzene) and
a
greater amount (60%) of diazide (2,4-diazido-
3-nitrobenzene).
Under mw irradiation, the SNAr substitution in
para-nitro halogenated benzene (F, Cl, and Br) must
An organic solution of halogenated nitrobenzene
(1 mmol) in DMF (6 ml) and an inorganic solution of
sodium azide (1 mmol) in water (2 ml) were placed in a
flask. The resulting reaction mixture was stirred and
heated with a hot water bath at mild temperature (50ꢀC
to 70ꢀC) for several hours (10–20). In each case, the
minimal temperature to induce reaction was determined
experimentally. After cooling, a volume (20 ml) of cold
water was added and the mixture was placed in an
ice-water bath for 30 min to induce precipitation. The
solid aryl azide was separated by filtration and purified
by column chromatography on a silica column using a
mixture hexane/ethyl acetate (70/30) as the eluent
solvent.
follow
a classical addition–elimination mechanism
because its rate decreases (F > Cl > Br) when atom
size increase and electronegativity decrease. However,
this same reaction takes place rather fast for a larger
and less electronegative Iodo atom (I > Cl > Br). In
this latter case, it must follow a concerted mechanism
for a highly polarizable atom. Because SNAr methodol-
ogies could undergo either a concerted or a classical
addition–elimination mechanism they could be applied
in the preparation of other derivatives, studies are in
progress to investigate the synthesis of different
substituted aromatic compounds using the methodolo-
gies described in here.
4.3 | Preparation of nitrophenyl azides
by SNAr reaction under phase-transfer
conditions
4 | EXPERIMENTAL
4.1 | General procedures
An organic solution of halogenated nitrobenzene
(1 mmol) in DMF (6 ml) and an inorganic solution of
containing sodium azide (1 mmol) and PTC (TEATFB,
0.1 mmol) in water (2 ml) were placed in a flask. The
reaction mixture was heated in a hot water bath at mild
temperature (50ꢀC to 70ꢀC) for several hours (4–10).
After this time, the reaction mixture was placed in a
water bath for cooling. Then, it was added 20 ml of cold
water, and it was placed in an ice-water bath for 30 min
to induce precipitation. A crystalline solid precipitated
and was separated by filtration and recrystallized in
ethanol.
Caution! Organic azides should be considered explosive.
Because they are thermally, photochemically, and
frictionally sensitive, their manipulation should take
place behind a blast shield and under diminished
light.[13]
All the starting halogenated benzenes, solvents, and
other reagents were obtained from commercial suppliers.
The PTC used was TEATFB ((C2H5)4N+(BF4)−). Melting
points were measured with a Fisher Johns apparatus.
UV-VIS spectra were obtained on a Shimadzu UV-2401
PC spectrophotometer. IR spectra were recorded on a
Nicolet 15-10 Thermo Scientific FTIR spectrophotometer.
1H NMR spectra were obtained on a Mercury 400-MHz
spectrometer. HRMS analysis was performed on a
Finnigan MAT 8400 mass spectrometer. Reactions under
microwave irradiation were performed in a CEM micro-
wave reactor, Discover System DU8756. All the azides
reported in this article have been prepared by other
methodologies, and they were characterized by UV-VIS,
IR, NMR spectroscopy, and mass spectrometry to confirm
their structure.[2,3,8–13,16,31,32] All aryl azides give two
strong bands in IR (around 2100 cm−1) due to symmetric
and asymmetric stretching of azide group (N3). The
purity of aryl azides was verified by melting point and/or
1H NMR spectroscopy.
4.4 | Preparation of nitrophenyl azides
by SNAr reaction under microwave heating
An organic solution of halogenated nitrobenzene
(1 mmol) in DMF (6 ml) and an inorganic solution of
sodium azide (1 mmol) in water (2 ml) were placed in a
flask. The resulting reaction mixture was irradiated in a
microwave reactor (at 50 W) and mild temperature (50ꢀC
to 70ꢀC) for several minutes (5–50). After this time, it was
added 20 ml of cold water and was placed in an ice-water
bath for 30 min to induce precipitation. The solid
crystalline aryl azide was separated by filtration and
recrystallized in ethanol.

LEYVA ET AL.
11 of 12
4.5 | Preparation of fluorophenyl azides
by SNAr reaction under conventional
heating
ACKNOWLEDGMENTS
Support for this work by CONACyT (Grant 155678) is
gratefully acknowledged. Johana Aguilar thanks
CONACyT for M.Sc. Scholarship (CVU 1007105).
An organic solution of a pF compound (1 mmol) in
acetone (6 ml) and an inorganic solution of sodium azide
(1 or 5 mmol) in water (2 ml) were placed in a flask
equipped with a reflux condenser. The mixture was
stirred at mild temperature (25ꢀC or 40ꢀC) for several
hours (10–12). After cooling, the reaction mixture was
poured into 20 ml of cold water and the aryl azide
was extracted with ether. The organic extract was dried
over anhydrous MgSO4, filtered, and concentrated. Each
azide was purified by column chromatography on a silica
column using a mixture hexane/ethyl acetate (70/30) as
the eluent solvent.
ORCID
Elisa Leyva https://orcid.org/0000-0003-3281-2460
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4.7 | Preparation of fluorophenyl azides
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How to cite this article: Leyva E, Aguilar J,
González-Balderas RM, Vega-Rodríguez S, Loredo-
Carrillo SE. Synthesis of nitrophenyl and
fluorophenyl azides and diazides by SNAr under
phase-transfer or microwave irradiation: Fast and
mild methodologies to prepare photoaffinity
labeling, crosslinking, and click chemistry
reagents. J Phys Org Chem. 2020;e4171. https://doi.
org/10.1002/poc.4171